A male mutation bias is observed across vertebrates, and, where data are available, this bias is accompanied by increased per-generation mutation rates with parental age. While continuing mitotic cell division in the male germline post-puberty has been proposed as the major cellular mechanism underlying both patterns, little direct evidence for this role has been found. Understanding the evolution of the per-generation mutation rate among species requires that we identify the molecular mechanisms that change between species. Here, we study the per-generation mutation rate in an extended pedigree of the brown (grizzly) bear, Ursus arctos horribilis. Brown bears hibernate for one-third of the year, a period during which spermatogenesis slows or stops altogether. The reduction of spermatogenesis is predicted to lessen the male mutation bias and to lower the per-generation mutation rate in this species. However, using whole-genome sequencing, we find that both male bias and per-generation mutation rates are highly similar to that expected for a non-hibernating species. We also carry out a phylogenetic comparison of substitution rates along the lineage leading to brown bear and panda (a non-hibernating species) and find no slowing of the substitution rate in the hibernator. Our results contribute to accumulating evidence that suggests that male germline cell division is not the major determinant of mutation rates and mutation biases. The results also provide a quantitative basis for improved estimates of the timing of carnivore evolution.

A male mutation bias is observed across vertebrates, and, where data are available, this bias is accompanied by increased per-generation mutation rates with parental age. While continuing mitotic cell division in the male germline post-puberty has been proposed as the major cellular mechanism underlying both patterns, little direct evidence for this role has been found. Understanding the evolution of the per-generation mutation rate among species requires that we identify the molecular mechanisms that change between species. Here, we study the per-generation mutation rate in an extended pedigree of the brown (grizzly) bear, Ursus arctos horribilis. Brown bears hibernate for one-third of the year, a period during which spermatogenesis slows or stops altogether. The cessation of spermatogenesis is predicted to lessen the male mutation bias and to lower the per-generation mutation rate in this species. However, using whole-genome sequencing, we find that both male bias and per-generation mutation rates are the same as expected for a non-hibernating species. We also carry out a phylogenetic comparison of substitution rates along the lineage leading to brown bear and panda (a non-hibernating species) and find no slowing of the substitution rate in the hibernator. Our results contribute to accumulating evidence that suggests that male germline cell division is not the major determinant of mutation rates and mutation biases. The results also provide a quantitative basis for improved estimates of the timing of carnivore evolution.

Despite the increasing abundance of whole transcriptome data, few methods are available to analyze global gene expression across phylogenies. Here, we present a new software package (CAGEE) for inferring patterns of increases and decreases in gene expression across a phylogenetic tree, as well as the rate at which these changes occur. In contrast to previous methods that treat each gene independently, CAGEE can calculate genome-wide rates of gene expression, along with ancestral states for each gene. The statistical approach developed here makes it possible to infer lineage-specific shifts in rates of evolution across the genome, in addition to possible differences in rates among multiple tissues sampled from the same species. We demonstrate the accuracy and robustness of our method on simulated data, and apply it to a dataset of ovule gene expression collected from multiple self-compatible and self-incompatible species in the genus Solanum to test hypotheses about the evolutionary forces acting during mating system shifts. These comparisons allow us to highlight the power of CAGEE, demonstrating its utility for use in any empirical system and for the analysis of most morphological traits. Our software is available at https://github.com/hahnlab/CAGEE/.

Despite the increasing abundance of whole transcriptome data, few methods are available to analyze global gene expression across phylogenies. Here, we present a new software package (CAGEE) for inferring patterns of increases and decreases in gene expression across a phylogenetic tree, as well as the rate at which these changes occur. In contrast to previous methods that treat each gene independently, CAGEE can calculate genome-wide rates of gene expression, along with ancestral states for each gene. The statistical approach developed here makes it possible to infer lineage-specific shifts in rates of evolution across the genome, in addition to possible differences in rates among multiple tissues sampled from the same species. We demonstrate the accuracy and robustness of our method on simulated data, and apply it to a dataset of ovule gene expression collected from multiple self-compatible and self-incompatible species in the genus Solanum to test hypotheses about the evolutionary forces acting during mating system shifts. These comparisons allow us to highlight the power of CAGEE, demonstrating its utility for use in any empirical system and for the analysis of most morphological traits. Our software is available at https://github.com/hahnlab/CAGEE/.

Biological differences between males and females lead to many differences in physiology, disease, and overall health. One of the most prominent disparities is in the number of germline mutations passed to offspring: human males transmit three times as many mutations as do females. While the classic explanation for this pattern invokes differences in post-puberty germline replication between the sexes, recent whole-genome evidence in humans and other mammals has cast doubt on this mechanism. Here, we review recent work that is inconsistent with a replication-driven model of male-biased mutation, and propose an alternative, “faulty male” hypothesis. Importantly, we suggest that the new model for male-biased mutation may also help to explain several pronounced differences between the sexes in cancer, aging, and DNA repair. Although the detailed contributions of genetic, epigenetic, and hormonal influences of biological sex on mutation remain to be fully understood, a reconsideration of the mechanisms underlying these differences will lead to a deeper understanding of evolution and disease.